1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to indole acetic acid compounds which function as antagonists of the CRTH2 receptor. The invention also relates to the use of these compounds to inhibit the binding of prostaglandin D2 and its metabolites to the CRTH2 receptor and to treat disorders responsive to such inhibition.
2. Related Art
The Chemoattractant Receptor-homologous molecule expressed on T-Helper type 2 cells (CRTH2) receptor binds prostaglandin D2 (PGD2) and its metabolites. Efforts have been made to inhibit the binding of PGD2 and other ligands to the CRTH2 receptor in order to treat disorders and diseases related to excess activation of CRTH2.
Elevated PGD2 is thought to play a causative role in both asthma and atopic dermatitis. For example, PGD2 is one of the major prostanoids released by mast cells in the asthmatic lung and this molecule is found at high levels in the bronchial fluid of asthmatics (Liu et al., Am. Rev. Respir. Dis. 142:126 (1990)). Evidence of a role of PGD2 in asthma is provided by a recent publication examining the effects of overexpression of prostaglandin D synthase on induction of allergic asthma in transgenic mice (Fujitani, J. Immunol. 168:443 (2002)). After allergen challenge, these animals had increased PGD2 in the lungs, and the number of Th2 cells and eosinophils were greatly elevated relative to non-transgenic animals. These results are consistent with PGD2 being a primary chemotactic agent in the recruitment of inflammatory cells during allergic asthma.
PGD2 can bind to two G-protein coupled receptors, DP (Boie et al., J. Biol. Chem. 270:18910 (1995)) and CRTH2 (Nagata et al., J. Immunol. 162:1278 (1999); Hirai et al., J. Exp. Med. 193:255 (2001)). The latter receptor might play a particularly important role in diseases such as asthma and atopic dermatitis that are characterized by Th2 cell involvement, since Th2 cell chemotaxis in response to PGD2 appears to be mediated by CRTH2 (Hirai et al., above). Moreover, eosinophils, the major inflammatory cell type seen in asthmatic lungs, show a CRTH2-mediated chemotactic response to PGD2 (Hirai et al.) and certain thromboxane metabolites (Bohm et al., J. Biol. Chem. 279:7663 (2004)).
WO 03/066046 discloses compounds of the following formula which are active at the CRTH2 receptor:
wherein:    R1 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy,    R2 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy;    R3 is hydrogen, C1-6 alkyl;    R4 is hydrogen, C1-6 alkyl, C1-6 alkoxy, thio C1-6 alkyl; and    X is N or CH.
WO 03/66047 discloses compounds of the following formula which are active at the CRTH2 receptor:
wherein:    R1 is a 1,3-benzothiazole group optionally substituted by halogen, C1-6 alkyl, C1-6 alkoxy, or a group of Formula (A) or (B):
where R4 and R5 are independently halogen, C1-6 alkyl, C1-6 alkoxy, phenoxy optionally substituted by halogen, C1-6 alkyl, C1-6 alkoxy,
where one of X and Y is nitrogen and the other is nitrogen, oxygen, or sulfur and R6 is phenyl optionally substituted by halogen, C1-6 alkyl, C1-6 alkoxy;    R2 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy; and    R3 is hydrogen, C1-6 alkyl.
WO 03/101961 discloses compounds of the following formula which are active at the CRTH2 receptor:
wherein:    R1 is hydrogen, halogen, CN, nitro, SO2R4, OH, OR4, S(O)xR4, SO2NR5R6, CONR5R6, NR5R6, aryl (optionally substituted by chlorine or fluorine), C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkyl, the latter three groups being optionally substituted by one or more substituents independently selected from halogen, OR8 and NR5R6, S(O).R7 where x is 0, 1, or 2;    R2 is hydrogen, halogen, CN, SO2R4 or CONR5R6, CH2OH, CH2OR4 or C1-C7 alkyl, the latter group being optionally substituted by one or more substituents independently selected from halogen atoms, OR8 and NR5R6, S(O).R7 where x is 0, 1, or 2;    R3 is aryl or heteroaryl each of which is optionally substituted by one or more substituents independently selected from hydrogen, halogen, CN, nitro, OH, SO2R4, OR4, SR4, SOR4, SO2NR5R6, CONR5R6, NR5R6, NHCOR4, NHSO2R4, NHCO2R4, NR7SO2R4, NR7CO2R4, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkyl, the latter three groups being optionally substituted by one or more substituents independently selected from halogen, OR8 and NR5R6, S(O)xR7 where x is 0, 1, or 2;    R4 represents aryl, heteroaryl, or C1-C6 alkyl all of which may be optionally substituted by one or more substituents independently selected from halogen atoms, aryl, heteroaryl, OR10, OH, NR14R12, S(O)xR13 (where x=0, 1, or 2), CONR14R15, NR14COR15, SO2NR14R15, NR14SO2R15, CN, nitro;    R5 and R6 independently represent a hydrogen atom, a C1-C6 alkyl group, or an aryl, or a heteroaryl, the latter three of which may be optionally substituted by one or more substituents independently selected from halogen atoms, aryl, OR8 and NR14R15, CONR14R15, NR14COR15, SO2NR14R15, NR14SO2R15, CN, nitro; or    R5 and R6 together with the nitrogen atom to which they are attached can form a 3-8 membered saturated heterocyclic ring optionally containing one or more atoms selected from O, S(O), where x=0, 1, or 2, NR16, and itself optionally substituted by C1-C3 alkyl;    R7 and R13 independently represent a C1-C6 alkyl, an aryl or a heteroaryl group, all of which may be optionally substituted by halogen atoms;    R8 represents a hydrogen atom, C(O)R9, C1-C6 alkyl, an aryl or a heteroaryl group, all of which may be optionally substituted by halogen atoms;    each of R9, R10, R11, R12, R14, R15, independently represents a hydrogen atom, C1-C6 alkyl, an aryl or heteroaryl group (all of which may be optionally substituted by halogen atoms); and    R16 is hydrogen, C1-C4 alkyl, COC1-C4 alkyl, COYC1-C4 alkyl where Y is O or NR7,    provided that when R1 is hydrogen and R2 is methyl, then R3 is not 2-nitrophenyl.
WO 03/101981 discloses compounds of the following formula which are active at the CRTH2 receptor:
wherein:    R1 is hydrogen, halogen, CN, nitro, SO2R4, OH, OR4, SR4, SOR4, SO2NR5R6, CONR5R6, NR5R6, NR9SO2R4, NR9CO2R4, NR9COR4, heteroaryl, aryl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkyl, the latter five groups being optionally substituted by one or more substituents independently selected from halogen, OR8 and NR5R6, S(O)xR7 where x is 0, 1, or 2;    R2 is hydrogen, halogen, CN, SO8R4 or CONR5R6, CH2OH, CH2OR4 or C1-C7 alkyl, the latter group being optionally substituted by one or more substituents independently selected from halogen atoms, OR8 and NR5R6, S(O)yR7 where x is 0, 1, or 2;    R3 is aryl or heteroaryl each of which is optionally substituted by one or more substituents independently selected from hydrogen, halo-en, CN, nitro, OH, SO2R4, OR4, SR4, SOR4, SO2NR5R6, CONR5R6, NR5R6, NR9SO2R4, NR9CO2R4, NR9CO2H, NR9COR4, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, the latter three groups being optionally substituted by one or more substituents independently selected from halogen atoms, OR8 and NR5R6, S(O)xR7 where x is 0, 1, or 2; with the proviso that R3 cannot be phenyl or substituted phenyl;    R4 represents aryl, heteroaryl, or C1-C6 alkyl all of which may be optionally substituted by one or more substituents independently selected from halogen atoms, aryl, heteroaryl, OR10, and NR11R12, S(O)xR3 (where x=0, 1, or 2), CONR14R15, NR14COR15, SO2NR14R15, NR14SO2R15;    R5 and R6 independently represent a hydrogen atom, a C1-C6 alkyl group, or an aryl, or a heteroaryl, the latter three of which may be optionally substituted by one or more substituents independently selected from halogen atoms, aryl, OR8 and NR14R15, CONR14R15, NR14COR15, SO2NR14R15, NR14SO2R15; or    R5 and R6 together with the nitrogen atom to which they are attached can form a 3-8 membered saturated heterocyclic ring optionally containing one or more atoms selected from O, S(O)x where x=0, 1, or 2, NR6, and itself optionally substituted by C1-C3 alkyl;    R7 and R13 independently represent a C1-C6 alkyl, an aryl or a heteroaryl group, all of which may be optionally substituted by halogen atoms;    R8 represents a hydrogen atom, C(O)R9, C1-C6 alkyl, an aryl or a heteroaryl group, all of which may be optionally substituted by halogen atoms or an aryl group;    each of R9, R10, R11, R2, R14, R15, independently represents a hydrogen atom, C1-C6 alkyl, an aryl or heteroaryl group (all of which may be optionally substituted by halogen atoms); and    R16 is hydrogen, C1-C4 alkyl, COC1-C4 alkyl, COYC1-C4 alkyl where Y is O or NR7.
WO 2004/007451 discloses compounds of the following formula which are active at the CRTH2 receptor:
wherein:    n represents 1 or 2;    R1 is one or more substituents independently selected from halogen, CN, nitro, SO2R4, OR4, SR4, SOR4, SO2NR5R6, CONR5R6, NR5R6, NR9SO2R4, NR9CO2R4, NR9COR4, aryl, heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkyl, the latter five groups being optionally substituted by one or more substituents independently selected from halogen, OR7 and NR8R9, S(O)xR7 where x is 0, 1, or 2;    R2 is hydrogen, halogen, CN, SO2R4 or CONR5R6, COR4 or C1-C7 alkyl the latter group being optionally substituted by one or more substituents independently selected from halogen atoms, OR8 and NR5R6, S(O)xR7 where x is 0, 1, or 2;    R3 is aryl or a 5-7 membered heteroaryl ring containing one or more heteroatoms selected from N, S, and O, each of which is optionally substituted by one or more substituents independently selected from halogen, CN, nitro, SO2R4, OH, OR4, SR4, SOR4, SO2NR5R6, CONR5R6, NR5R6, NR9SO2R4, NR9CO2R4, NR9COR4, C2-C6 alkenyl, C2-C6 alkynyl C1-C6 alkyl, the latter three groups being optionally substituted by one or more substituents independently selected from halogen atoms, OR7 and NR5R6, S(O)xR7 where x is 0, 1, or 2;    R4 represents aryl, heteroaryl, or C1-C6 alkyl all of which may be optionally substituted by one or more substituents independently selected from halogen atoms, aryl, heteroaryl, OR10, and NR11R12, S(O)xR13 (where x=0, 1, or 2), CONR14R15, NR14COR15, SO2NR14R11, NR14SO2R5, CN, nitro;    R5 and R6 independently represent a hydrogen atom, a C1-C6 alkyl group, an aryl, or a heteroaryl, the latter three of which may be optionally substituted by one or more substituents independently selected from halogen atoms, aryl, OR13 and NR14R15, CONR14R15, NR14COR15, SO2NR14R15, NR14SO2R5, CN, nitro; or    R5 and R6 together with the nitrogen atom to which they are attached can form a 3-8 membered saturated heterocyclic ring optionally containing one or more atoms selected from O, S(O), where x=0, 1, or 2, NR16, and the ring itself optionally substituted by C1-C3 alkyl;    R7 and R13 independently represent a C1-C6 alkyl, an aryl or a heteroaryl group, all of which may be optionally substituted by halogen atoms;    R8 represents a hydrogen atom, C(O)R9, C1-C6 alkyl (optionally substituted by halogen atoms, aryl or heteroaryl groups, both of which may also be optionally substituted by one or more fluorine atoms), an aryl or heteroaryl group, which may be optionally substituted by one or more halogen atoms;    each of R9, R10, R11, R12, R14, R15, independently represents a hydrogen atom, C1-C6 alkyl, an aryl or a heteroaryl group (all of which may be optionally substituted by halogen atoms); and    R16 is hydrogen, C1-C4 alkyl, COC1-C4 alkyl, C(O)YC1-C4 alkyl, Y is O or NR7.
WO 02/060438 discloses compounds of the following formula that can be used as integrin antagonists:
wherein R1, R2, R3, R4, and R5 independently represent hydrogen, halogen, alkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;    R6, R7, R8, and R9 independently represent hydrogen, alkyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, aryl, or aralkyl;    or R6 and R7 are taken together to form —(CH2)p—, where p is 2-8, while R8 and R9 are defined as above; or R9 and R9 are taken together to form —(CH2)q—, where q is 2-8, while R6 and R7 are defined as above; or R6 and R8 are taken together to form —(CH2)r—, while r is zero (a bond), 1, or 2, while R7 and R9 are defined as above;    X represents oxygen, sulfur, —CH2—, —NH—, —(C═O)NH—, or —NH(C═O)—;    n is from 0 to 4;    m is from 0 to 4;    a is 0 or 1;    D represents oxygen;    V is 0 or 1;    R10, R11, R12, and R13 independently represent: hydrogen; hydroxy; alkyl; alkoxy; cycloalkyl; aryl, optionally substituted with one or more of halogen, hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl, arylalkyl, arylalkoxy, aryloxy, alkylsulfonyl, alkylsulfinyl, alkoxyarylalkyl, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkanoyl; monoalkylamino; dialkylamino; aminoalkyl; monoalkylaminoalkyl; dialkylaminoalkyl; alkanoyl; heteroaryl having 5-14 ring members, optionally substituted with one or more of halogen, hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl, arylalkyl, arylalkoxy, aryloxy, alkylsulfonyl, alkylsulfinyl, alkoxyarylalkyl, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkanoyl; or
wherein R17 and R18 together form —CH2CH2—O—, —O—CH2CH2—, —O—CH2—O—, or —O—CH2CH2—O—; or    R10 and R12 are taken together to form —(CH2)s—, wherein s is 0 (a bond) or 1 to 4, while R11 and R13 are defined as above; or R10 and R12 are taken together to form a double bond when i is 0 and k is 1, while R11 and R13 are as defined above; or R10 and R11 are taken together to form —(CH2)t—, wherein t is 2 to 8, while R12 and R13 are defined as above, or R12 and R13 are taken together to form —(CH2)u— wherein u is 2 to 8, while R10 and R11 are defined as above;    i is from 0 to 4;    j is from 0 to 4;    k is 0 or 1;    R14 is hydrogen or a functionality that acts as a prodrug;    W is
wherein Y is —N— or —CH—;    Z is —N— or —CH—;    R15 is hydrogen, halogen, alkyl, aryl, or arylalkyl;    R16 is hydrogen, alkyl, haloalkyl, or halogen;    R19 and R20 are independently hydrogen, halogen, or alkyl;    R27, R28, R29, R30, and R31 are independently hydrogen, halogen, alkyl, alkoxy or aryl; and    o and p are independently 0, 1, or 2.